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Drug Use in Patients with Renal Failure

ABSTRACT In general, dosage adjustment in RF is not required when (a) renal elimination of the drug is <33%, and the metabolites are not active, or (b) GFR is still > 50 mL/min, and for most antibiotics, when GFR is still > 20 mL/min. For drugs with narrow margin of safety and the main elimination is by renal excretion (e.g. aminoglycosides, vancomycin, digoxin), dosage adjustment is required in all degrees of RF. Drug dosage in RF can be estimated from calculation or dosing tables. Drug use in RF should be avoided if too risky (eg. tetracycline) and other safer drugs are available. The dosage estimation should be refined by titration of efficacy and safety in individual patients. Supplemental dose postHD is required when HD clearance is at least 30% of total body clearance. Predictably, this is for drugs with MW < 500 D, water soluble, uncharged, minimal protein binding, and Vd < 1 L/kg. Alteration in pharmacokinetics and pharmacodynamics of drugs in RF causes increased risk of adverse drug reactions. Multiple medications in patients with RF cause increased drug interactions in these patients.

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be distributed to the receptors where they tional nephrons. In renal failure, the functional fusible. Diffusivity decreases as drug molecular act, and to the organs of elimination where nephron mass decreases, causing a decrease weight increases. Drugs with MW more than they are eliminated, leading to decreased to- in glomerular filtration. For example, ampicil- 1.000 Dalton (very few drugs) have negligible tal plasma concentration. Edema or ascites in lin, aminoglycosides, and digoxin are excreted diffusive clearance, while small solutes have renal failure causes increased volume of distri- mainly by glomerular filtration. Ampicillin has flow-dependent clearance, and larger mol- bution of water soluble drugs, while volume a large margin of safety, and decreased glom- ecules have decreased diffusion rate. Charged contraction decreases volume of distribution erular filtration is compensated by increased drugs are less dialyzable because of charged of aminoglycosides and increases its plasma biliary excretion, therefore a decrease in dos- repulsion at the membrane surface and drug concentration. Digoxin is accumulated in age is required only when the GFR is less than binding to the membrane. muscles, therefore muscle wasting in patients 20 mL per minute. On the other hand, amino- with renal failure causes a decrease in its vol- glycosides and digoxin have low therapeutic Supplemental dose after HD is required if sig- ume of distribution and an increase in its plas- ratios, and therefore their dosage should be nificant drug removal occurs during HD. Drugs ma concentration. decreased in all degrees of renal failure. Dys- with MW less than 500 Dalton, that are water function of tubular secretion will cause a de- soluble and unchanged, having minimal pro- Metabolism crease in excretion of drugs actively secreted tein binding and volume of distribution less For drugs that are metabolized completely by by proximal renal tubule. Organic acids, such than 1 L/kg, undergo significant removal. the liver to inactive metabolites, no dosage as conjugates and free fatty acids, accumulate adjustment is required in patients with renal in renal failure. They will inhibit secretion of HD clearance is clinically significant if it in- failure. Phase II metabolism or conjugation other organic acids that are also secreted by creases total body clearance by 30 to 50%. reactions are normal in renal failure. Among proximal renal tubule because of competition Since dose is plasma concentration times vol- phase I reactions, the microsomal oxidation is for the same efflux transporter, P-glycoprotein. ume of distribution (Vd), then normal or accelerated (due to accumulation For example, the renal secretion of penicillins, Supplemental dose of inducers). Meanwhile, reduction (e.g. corti- cephalosporins, sulfonamides, nitrofurantoin, = (desired concentration concentration postHD) x Vd sol), peptide hydrolysis (e.g. insulin, glucagon thiazides and furosemide is inhibited. The and PTH), and ester hydrolysis (e.g. diflunisal competition of organic bases is usually not Peritoneal dialysis (PD) is very inefficient in and procaine), are slowed due to decreased clinically important. removing drugs, e.g. 1 HD treatment can re- nonhepatic (especially renal) metabolism. move 2/3 of body stores of aminoglycosides, Passive tubular reabsorption is only for nonionic while 24-hour CAPD (continuous ambulatory Excretion lipid soluble drugs. It is affected by urinary flow peritoneal dialysis) removes only 25 30% of Renal excretion consists of glomerular filtra- rate and urinary pH. In renal failure, the urinary the drug. tion, active tubular secretion, and active and flow decreases, but the tubular concentrations passive tubular reabsorption. Examples of of drugs also decrease, and hence the passive Table 2 Drugs requiring supplemental doses after each HD drugs mainly eliminated by renal excretion can tubular reabsorption is not affected. session be seen in Table 1. These drugs are excreted Aminoglycosides by the kidneys in unchanged form, and hence Accumulation of toxic metabolites in renal failure Cephalosporins (most) they will accumulate in renal failure, causing leads to increased adverse drug reactions, e.g. Penicillins (most) increased intensity of their pharmacological accumulation of toxic metabolite of meperidine Sulfonamides, TMP effects and toxicity; therefore their dosage causes seizures, that of nitrofurantion causes Ofloxacin, Ciprofloxacin should be reduced in renal failure. peripheral neuropathy, while that of morphine Metronidazole causes excess respiratory depression. Flucytosine Table 1 Drugs mainly eliminated by renal excretion Ethambutol, INH Nitrofurantoin End-stage renal disease (ESRD) means glom- Pyrazinamide Penicillins erular filtration is diminished to almost none. In Aciclovir, Ganciclovir Cephalosporins this situation, tubular secretion of acidic drugs is Zidovudine, Didanosine Aminoglicosides much decreased due to competition with high Diuretics accumulation of organic acids, and therefore di- Dosage Adjustment in Renal Failure Tetracyclines (Avoid !) alysis is required. Drugs excreted by glomerular Drug elimination by the kidney is assumed to Sulfonamides filtration, are water soluble and hence at least be directly proportional to GFR (glomerular ACE inhibitors partially dialyzable, while drugs excreted by tu- filtration rate); and ClCr (creatinine clearance) is Digoxin bular secretion are or are not dialyzable. traditionally used to approximate GFR. Cock- Ethambutol roft & Gault formula calculates ClCr from CCr Atenolol HEMODIALYSIS (HD) (creatinine plasma concentration). Disopyramide Since dialysate is aqueous, only water soluble drugs are dialyzable. HD procedure is mostly For men: ClCr (mL/min) = Only unbound drugs with molecular weight based on diffusion of solutes through mem- less than 60.000 Dalton are filtered by func- brane pores, and only unbound drugs are dif- For women: 0.85 x ClCr for men

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hypersensitivity, resulting in interstitial nephri- anion pump in the renal tubule. In azotemia, d. Antituberculosis drugs tis. Long-term use of NSAIDs can cause renal organic acids compete for the active transport, Isoniazid, rifampicin and pyrazinamide are giv- papillary necrosis. therefore the dosage should be increased by en in normal doses in RF. With isoniazid, pyri- doubling doses every 30 to 60 minutes until doxine should be added to prevent peripheral Avoid usage in high-risk patients, i.e. elderly or ceiling dose is reached or diuresis occurs. If neuropathy. compromised renal blood flow and volume this is ineffective, thiazide should be added. depletion with concomitant urinary tract in- If it is still ineffective, loop diuretics should be Streptomycin and ethambutol should be fection. If use is necessary, especially for long- given as continuous i.v. infusion. avoided where possible. The major toxicity term use, close monitoring of ClCr and regular of streptomycin is vestibular, therefore if re- urinalysis are required. b. Thiazides are generally not effective when quired, a reduced dose should be given 2 or ClCr is less than 25 mL/min. 3 times weekly for the first 2 months, and the 2. Analgesics plasma levels must be monitored. Acetaminophen is a safe analgesic, but not c. Ototoxicity. Especially ethacrynic acid, but always effective. Opiates are used for more se- also furosemide and bumetamide. Ethambutol causes optic neuritis if excessive vere pain, but retention of active metabolites dosages are used or renal function is im- causes prolonged analgesia and respiratory 5. Antimicrobial agents (AMs) paired. Therefore the dose should be reduced depression. Except aminoglycosides and vancomycin, most and given intermittently. If any visual changes AMs have a wide therapeutic index, hence little develop, the drug should be discontinued Analgesic nephropathy can be avoided by us- or no dosage adjustment is normally made un- immediately and medical advice must be ing a single analgesic, not a mixture of more til the GFR is less than 20 mL/min. sought. than 1 analgesic, especially in combination with caffeine or codeine. AMs that are removed by dialysis should be e. Amphotericin B administered after dialysis or a supplemental This drug is nephrotoxic. The drug is used 3. Cardiovascular drugs dose should be given after dialysis. in renal failure only if these is no alternative, a. Angiotensin converting enzyme (ACE) and plasma levels and renal function must be inhibitors and angiotensin receptor block- a. Aminoglycosides (AGs) monitored closely. Since binding to lipopro- ers (ARBs). Use in pre-existing renal disease The bactericidal efficacy correlates with thera- teins decreases in RF, low plasma levels should due to atherosclerosis (compromised renal peutic peak concentrations, while toxicity cor- be interpreted accordingly. perfusion), and also pre-existing peripheral, responds to rising trough levels. Therefore, the cerebral, or coronary vascular diseases associ- dosage adjustment should follow especially f. Antiviral drugs ated with renal dysfunction, which are usually the interval approach. Peak and trough serum Acyclovir and ganciclovir are eliminated by reversible on drug withdrawal. Accumulation levels as well as ClCr should be measured to kidney, therefore the dose should be reduced of these drugs in renal dysfunction requires monitor therapy and avoid toxicity. in RF, because accumulation leads to CNS tox- dosage reduction. Renal function should be icity and unconsciousness. checked 3 to 4 days after starting therapy to AGs aggravate pre-existing renal impairment, ensure no decreased in GFR or increased in but also cause de novo acute renal failure. 6. Antianxiety drugs, Hypnotics and Antipsy- serum potassium. Nephrotoxicity is usually reversible, but oto- chotics toxicity may cause irreversible vestibular dam- Patients with advanced RF are particularly b. Calcium channels blockers (CCBs) age. Concomitant use of loop diuretics, espe- sensitive to CNS depressant effect of these These drugs are eliminated by hepatic metab- cially ethacrynic acid, greatly increases the risk drugs, therefore therapy should be started olism, hence they are used in usual dosages of ototoxicity. with a smaller than normal dose. in RF. b. Vancomycin 7. Lithium and Antidepressants c. Digoxin This drug is nephrotoxic and ototoxic; there- Lithium should be avoided if possible or de- DL and DM should be reduced in RF, and plas- fore its plasma concentrations should be crease the dose with careful monitoring of ma concentrations should be monitored. monitored. It is not dialyzed, hence after a plasma levels. Tricyclic antidepressants and single i.v. infusion, therapeutic levels can be newer antidepressants can be prescribed in d. -blockers maintained for 5 days in patients with end- normal dosages. The dose of -blockers that is mainly elimi- stage RF on dialysis. nated by kidney should be reduced. 8. Insulin c. Tetracyclines In reduced renal function, insulin requirement 4. Diuretics These drugs greatly increase BUN in RF due is also reduced, because it is eliminated by the a. Loop diuretics are required to avoid vol- to its antianabolic effects and worsen the re- kidney. In uremia, these is insulin resistance ume overload. These drugs have extensive nal dysfunction. Therefore use of these drugs due to a post-receptor defect; this is corrected protein binding, therefore are not much fil- should be avoided in RF, except doxycycline by dialysis. The compensatory response to hy- tered via glomerulus, but secreted by organic and minocycline. poglycemia may also be impaired in uremia.

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9. Oral antidiabetics (OADs) hence the dose should be reduced in severe GI hemorrhage, rashes and renal impairment, Since chlorpropamide has an extended half- RF. Proton pump inhibitors require no dosage hence the dose should be reduced in RF. life of > 36 hours, its use in RF should be avoid- adjustment in RF. ed. Glibenclamide also causes prolonged hy- NOTE poglycemia in RF due to accumulation of an b. Antacids Calculation of drug dosage in RF is based on active metabolite which binds tightly to pan- Antacids containing Mg and Al (including various assumptions, i.e. no change and no creatic -cells. sucralfate) should be avoided in severe RF or interindividual variation in drug absorption, dialysis patients because of increased risk of distribution, and metabolism; no active/toxic Metformin is contraindicated in RF because toxicity. metabolites; drug elimination independent the risk of lactic acidosis. of dose (linear pharmacokinetics); no change 11. Antigout drugs and no interindividual variation in pharma- Glipizide is the OAD of choice in RF because of Allopurinol is metabolized to oxypurinol. Its cological response; stable renal function; its short duration of action and its elimination accumulation in renal failure causes rashes (in and renal clearance of drug is proportional by hepatic metabolism to inactive metabo- severe case, it can cause potentially fatal toxic to ClCr. Therefore dosage adjustment based lites. epidermolysis), bone marrow depression and on calculation is only for initial estimation. It GI upset; therefore the daily dose should be should be followed by further adjustments 10. Gastrointestinal drugs reduced in RF. based on the plasma drug level (if available), a. Antiulcers and the most important on patients clinical Ranitidine is eliminated by liver and kidney, Colchicine in excessive doses causes diarrhea, response.